Natural immune responses to cancer are usually insufficient to prevent tumor growth. Immunotherapy for cancer seeks to enhance these immune responses and make them more effective. Current approaches include non-specific stimulation of the immune system, active immunization with tumor-specific antigens, and adoptive cell therapy-the transfer of tumor-specific T cells. Recently, we have investigated adoptive cell therapy to treat lymphoma1. The efficacy of this maneuver is impressive and cures large tumors. Specifically, we use active immunization to generate anti-tumor T cells and transfer these T cells into lymphodepleted recipient mice. We refer to the preparation of these cells and subsequent transfer as immunotransplant. Currently, we are developing a new vaccine to induce anti-tumor T cells. This vaccine combines tumor antigens with a non-specific immune stimulant: irradiated-tumor cells (a rich source of tumor antigens) are loaded with the TLR agonist, CpG (an immune stimulant). The T cells induced by this vaccine can mediate anti-tumor immune responses and are more effective when adoptively transferred into lymphodepleted mice. The studies proposed here will take advantage of our unique experimental model to address two important challenges facing adoptive cell therapy. Aim 1 will elaborate on the methods and mechanisms of inducing anti- tumor T cells. We are developing this therapy for evaluation in a clinical trial to treat mantle cell lymphoma. A better understanding of donor vaccination and continued validation of in vitro immune assays will impact the clinical trial design. Aim 2 will investigate the role of CD4 memory T cells in anti-tumor immunity. Specifically, we will attempt to describe a CD4 memory stem cell. It is well accepted that CD8 memory T cells possesses similar genetic profiles to long-term hematopoietic stem cells37. Recent work has characterized the functional role of this CD8 T cell population in anti-tumor immunity4. Our model system provides a unique opportunity to determine if a CD4 memory stem cell population exists and whether it is important for T cell-mediated anti- tumor immune responses. PUBLIC HEALTH RELEVANCE: Immunotherapy for cancer seeks to enhance natural immune responses against tumors and make them more effective. One approach-adoptive cell therapy-involves the transfer of tumor-specific T cells. The work proposed in this fellowship has two goals related to an adoptive cell therapy we developed for treating lymphoma: (1) investigating a new vaccine for generating anti-tumor T cells and (2) understanding the specific cell populations that mediate effective anti-tumor immune responses. These studies have direct clinical relevance and will contribute important knowledge to the field of cancer immunotherapy.